PI - Andrew Saxon MD Abstract: The goal of this SBIRI application is to accomplish key ?long term? safety and efficacy time-course studies of a novel biologic designed for the preventive treatment of all severe/IgE mediated food allergic reactions and mastocytosis. Allergic diseases and specifically severe food allergies have increased to the point of becoming a major worldwide public health problem, particularly in the US and other developed countries. Currently, effective novel treatment options for such allergies remain a major unmet need; no effective therapy is available for the broad array of severe food allergies (e.g. peanut, egg, milk etc. allergy). Our approach uniquely employs Low-affinity Allergy Response Inhibition (LARI) in the form of a carefully designed monoclonal antibody (LARI E59) that targets Fc?RI-bound IgE on human basophils and mast cells. The binding and release of LARI E59 functionally blocks the induction of allergic reactions by three distinct effects. LARI treatment is designed to be pan-allergen effective and work for all IgE driven food allergies. Additionally, LARI, because of its unique mechanism of action has been granted orphan drug designation for mastocytosis by the FDA. We have performed extensive proof-of-concept studies that demonstrate that LARI exhibits a potent blocking effect on allergic reactivity by rapidly inhibiting the activity of the key immediate allergic effector cells: basophils and mast cells while far higher doses of LARI fail to trigger anaphylactic degranulation. However, two key questions remain (1) Will repeated administration of LARI be safe? (2) What is the time course of the therapeutic effect of LARI? This proposal is designed to specifically answer these questions utilizing the now available complex immunodeficient mice reconstituted with human CD34+ stem cells that make IgE. To determine the safety of repeated injections of LARI reconstituted NSG-SMS mice that express human IgE will be injected four times with LARI over a time course that represents treatments over an approximate 6 month time course in humans. At each time point, mice will be carefully evaluated for evidence of allergic reactivity. To determine the time course for the efficacy of LARI, reconstituted NSG-SMS mice, sensitized to peanut by gavage, will be treated with LARI and then challenged with peanut at day +7, +14 or +21 after the treatment. This would test the efficacy of LARI after about one, two and three months in humans. Having accomplished these studies proposed, we will have answered two key remaining questions as the LARIs potential as a safe and effective therapeutic.